October 2004 Bulletin

FDA’s tissue action plan: Safeguarding the public

Agency overhauls its tissue regulation policies

By Michael J. Joyce, MD, and Donna Toohey

Transmission of disease in allograft tissue is a rare occurrence. Nonetheless, recent cases of infection reported by the Centers for Disease Control and Prevention (CDC) in 2002 and 20031 are of concern to orthopaedic surgeons. The 2001 death of a 23-year old Minnesota man from a Clostridium sordellii-infected ACL allograft initiated the CDC investigations. Physicians should be aware that the Food and Drug Administration (FDA) is in the final stages of establishing a public health safety net across all sectors of tissue processing, banking and procurement.

The 1997 U.S. General Accounting Office (GAO) report, “Human Tissue Banks: FDA Taking Steps to Improve Safety but Some Concerns Remain,” examined FDA’s regulatory oversight of transplanted human tissue to detect potential gaps or safety concerns.2 In response to the report, which identified significant public health shortcomings, the FDA initiated a comprehensive and strategic overhaul of its tissue regulation policies. FDA’s reinvention of its regulatory strategy led to the creation of an encompassing Tissue Action Plan (TAP).

FDA has three primary goals for the TAP: (1) to prevent the spread of communicable diseases; (2) to ensure that safety and efficacy are demonstrated for tissue and combination products (cellular- and tissue-based products that are also drug, biological and medical device products); and (3) to enhance public confidence in these products.3

TAP regulation is broadly classified into three areas of subject matter: registration and listing of tissue establishments, donor eligibility, and good tissue practices. Final rules on both registration and listing and donor eligibility have been issued. The current good tissue practices final rule is expected in early 2005.

Registration and listing

The final rule, “Human Cells, Tissues, and Cellular- and Tissue-Based Products: Establishment Registration and Listing” was published in the Federal Register in January 2001.4 The FDA broadened the scope of its regulatory powers to include human cells and cellular- and tissue-based products (HCT/Ps), in addition to tissue, so that innovative biological products of novel regulatory classification are not lost to oversight.

The rule requires all establishments that engage in the recovery, screening, testing, processing, storage or distribution of human tissue intended for transplantation to register with FDA. This rule encompasses two broad public health objectives. First, it facilitates a centralized listing of sites so that the FDA can rapidly communicate alerts of emergent disease threats or epidemiological trends that may affect the integrity of transplanted tissues. Second, from this list of all known U.S. tissue establishments, the FDA can identify sites for routine facility inspections.

Donor eligibility

In May 2004, the FDA published its final rule on “Eligibility Determination for Donors of Human Cells, Tissues, and Cellular- and Tissue-Based Products.”5 This rule requires that a tissue donor must be found eligible, based on the results of screening and testing for relevant communicable diseases, before the use of HCT/Ps, with exceptions for certain autologous or intimate partner donations.

The donor eligibility rule pertains not only to traditional tissue such as musculoskeletal, skin, and eyes, but also to reproductive tissue (i.e., semen, ova, embryos), hematopoietic stem cells derived from cord blood and peripheral blood, and cellular therapies. In addition to testing for HIV and Hepatitis viruses B (HBV) and C (HCV), all tissue also must be screened for human transmissible spongiform encephalopathies (TSEs), including Creutzfeldt-Jacob disease, and both screened and tested for syphilis. Reproductive tissues are subject to additional testing requirements. Donor eligibility determinations must be made and documented by the tissue establishment.

Current donor screening regulations mandate the use of FDA-licensed antibody tests for HIV, HBC and HCV. There exists a window of potential infectivity of donor tissue prior to donor production of specific antibodies. In June 2002, the Oregon Department of Public Health confirmed a case of acute Hepatitis C in the recipient of a patellar tendon with bone allograft from an HCV-seronegative donor. Of the 40 patients who received transplanted organs or tissues from the donor, eight were positively identified as having the same HCV genotype post-transplantation.6

Nucleic acid testing (NAT) is one method to supplement traditional serology antibody testing. NAT testing identifies viruses by their RNA, not by the presence of host antibodies. Though the FDA has recently licensed a NAT test for HIV and HCV in cadaveric serum (NAT testing for HBV is currently under investigation), the FDA is not yet requiring NAT testing for cadaveric specimens. The FDA has announced that as more evidence becomes available, it may issue recommendations for NAT testing in cadaveric tissue donors. The CDC has noted that postmortem serum might confer limitations on NAT testing for cadaveric tissues.7

On September 9, 2004, the American Association of Tissue Banks (AATB) approved a measure requiring AATB-accredited tissue banks to adopt NAT testing for HIV and HCV with FDA-licensed cadaveric assays as soon as possible, but no later than March 9, 2005. The AATB notes that NAT testing is supplemental to current antibody testing, and does not replace antibody testing for HIV and HCV viruses.

The donor eligibility rule also provides for the implementation of administrative safeguards, such as stringent record keeping intended to prevent or contain the spread of communicable disease. Because some diseases such as TSEs have long latency periods, the FDA requires a 10-year record retention period. This rule also provides a framework for identifying emergent diseases that may pose risks to the tissue supply (e.g., West Nile virus and severe acute respiratory syndrome), and allows the FDA the flexibility to assess and monitor establishment procedures with regard to rapid infectious threats as they occur.

Good tissue practices

The proposed rule on Current Good Tissue Practices (CGTPs) was published in January 2001, and the tissue industry is currently anticipating the projected early 2005 release of the final rule.8 The FDA received many comments in response to the proposed CGTP rule, which is being revised. CGTP requirements are intended to prevent the introduction, transmission and spread of communicable diseases by helping to ensure that: (1) products do not contain relevant communicable disease agents; (2) products are not contaminated during the manufacturing process; and (3) the function and integrity of the products are not impaired through improper manufacturing.

The proposed CGTP rule would require that cells and tissues be handled according to a “quality program” of procedures designed to prevent infection and preserve tissue integrity. Tissue establishments would need to develop and validate procedures for the proper handling, processing, storage, labeling and recordkeeping of cells and tissues.

The proposed CGTP rule provides for the collection of post-market safety data, and requires tissue establishments to report “adverse reactions.” An adverse reaction is defined as “a noxious and unintended response to any human cellular or tissue-based product for which there is a reasonable possibility that the response may have been caused by the product (i.e., this relationship cannot be ruled out).” In its comment to FDA, the AAOS challenged the definition of adverse reaction in the proposed rule as being too broad. Reportable adverse reactions noted in the proposed rule are those that are fatal, life-threatening, result in permanent impairment or damage, or necessitate medical or surgical intervention.

The proposed rule would also prohibit the pooling of human cells or tissues from two or more donors during manufacturing.

Certain practices pertaining to recovery, processing and storage of autograft tissue may be influenced by the final CGTP rule. The AAOS will analyze the implications of the final rule for the safety of the tissue supply as well as its impact upon orthopaedic practice.

Conclusion

In May 2004, the CDC reported four deaths attributable to the transplantation of organs from a rabies-infected donor.9 Diseases will continue to emerge and pose a threat to the blood and tissue supply. In that regard, the FDA Tissue Action Plan is a risk-based regulatory scheme with broad authority over cellular and tissue-based products, designed to protect the integrity of the U.S. tissue supply from traditional, opportunistic and emergent agents of disease.

Michael J. Joyce, MD, is a member of the AAOS Biological Implants Committee, which monitors regulatory and industry developments in tissue banking and safety, and reports developments to the Fellowship through educational and informational venues. He can be reached at joycem@ccf.org

Donna Toohey is a regulatory analyst in the AAOS department of research and scientific affairs. She can be reached at toohey@aaos.org